Major depressive disorder (MDD) is an etiologically and phenotypically complex disorder causing significant morbidity and mortality. MDD is often comorbid with HIV infection and is reported to be over-represented in this group compared to the general population. Our overarching hypothesis is that there is a biological basis for the co-occurrence of these conditions based on gene expression, molecular and cellular pathology. In support of this proposition, in HIV infected individuals with a documented history of MDD compared to those without MDD, we have demonstrated (see preliminary data) a significant decrease in the frontal cortical gene expression of somatostatin, fibroblast growth factor-2 (FGF2) and growth arrest and DNA-damage-inducible-beta (GADD45B), and an increase in gene expression of serum/glucocorticoid regulated kinase 1 (SGK1). SGK1 is regulated by glucocorticoids and stress, it is significantly increased in the brain during neurodegeneration, promotes dendritic growth and is involved in learning and memory. Gadd45B is also a stress response gene that is regulated by SGK1 and HIV. We have validated the loss of somatostatin gene expression by quantitative real-time polymerase chain reaction (qRT-PCR), which correlates with the density of calbindin immunopositive interneurons and we noted a significant decrease in the number of cortical somatostatin immunopositive neurons in a transgenic mouse MDDel producing the HIV regulatory nef protein (see preliminary data). Our observation of decreased FGF2 gene expression in HIV infected individuals with MDD has recently been observed in non-infected individuals with MDD {Evans, 2004 #782} and we have recapitulated the reduction in FGF2 in human brain aggregates exposed to cortisol (see preliminary data). An important goal of this proposal is to quantify our candidate somatostatin and stress-related gene expression (FGF2, GADD45A/B and SGK1) in human brain derived from persons who died with HIV, MDD and combined risks, as well as those who had neither risk. In this way we will establish whether commonalities exist between HIV and MDD at the gene expression level. We will also assess the expression of these candidate genes in HIV animal models and investigate the temporal expression of these genes in in vitro neuronal cultures. The data will provide a foundation for clarifying the underlying potential pathological mechanisms of MDD in HIV-infected individuals.